Intermediates for optically active piperidine derivatives and preparation methods thereof

ABSTRACT

A preparation method according to the present invention makes it possible to industrially produce large amounts of highly pure optically active tert-butyl 3-methyl-4-oxopiperidine-1-carboxylate in high yield by use of commercially available reagents and solvents. In addition, the use of novel intermediates according to the present invention makes it possible to produce highly pure optically active tert-butyl 3-methyl-4-oxopiperidine-1-carboxylate in high yield.

This application is a divisional, and claims priority, of co-pendingU.S. application Ser. No. 16/771,463, filed Jun. 10, 2020, which is aU.S. National Stage application, and claims priority of InternationalApplication No. PCT/KR2018/015559, filed Dec. 7, 2018, which claimspriority of South Korean Application Serial No. 10-2017-0169227, filedDec. 11, 2017. The contents of all of the prior applications areincorporated herein by reference in their entirety.

TECHNICAL FIELD

The present invention relates to intermediates for optically activepiperidine derivatives and preparation methods thereof.

BACKGROUND ART

Piperidine derivatives are widely used as key pharmacophores in thepharmaceutical and chemical fields. In particular, International PatentPublication Nos. WO 2004/041777, WO 2009/106534, WO 2008/119718, WO2010/051374, WO 2005/040169, WO 2013/021052, WO 2004/058709, WO2016/120849, WO 2014/023815, WO 2013/181579, WO 2016/120850 and the likedisclose tert-butyl 3-methyl-4-oxopiperidine-1-carboxylate as anintermediate for synthesizing various drugs, and also disclose themethods shown in Reaction Schemes I to III as methods for preparing theintermediate:

However, the intermediate compound disclosed in the above-mentionedpatent documents is a racemate, and the methods for preparing the samecan also prepare only a racemate. In addition, these patent documents donot disclose any method for preparing optically active Cert-butyl3-methyl-4-oxopiperidine-1-carboxylate.

However, pharmaceutical drugs may have significantly differentpharmacological activities and side effects, and for this reason, manypharmaceutical drugs have been developed as specific isomers.Preparation of pharmaceutical drugs using specific isomeric tert-butyl3-methyl-4-oxopiperidine-1-carboxylate as an intermediate have problemsarise in that it is economically inefficient due to a large amount ofconsumption of reagents and is not suitable for mass production due toits low production yield, compared to when pharmaceutical drugs areprepared using racemic tert-butyl 3-methyl-4-oxopiperidine-1-carboxylateas an intermediate.

Accordingly, the present inventors have developed a method capable ofindustrially producing large amounts of highly pure optically activetert-butyl 3-methyl-4-oxopiperidine-1-carboxylate, which is useful as anintermediate in the pharmaceutical and chemical fields, in high yield byuse of commercially available reagents and solvents, thereby completingthe present invention.

DISCLOSURE OF INVENTION Technical Problem

The present invention is intended to provide a method capable ofindustrially producing large amounts of highly pure optically activetert-butyl 3-methyl-4-oxopiperidine-1-carboxylate, which is useful as anintermediate in the pharmaceutical and chemical fields, in high yield byuse of commercially available reagents and solvents.

The present invention is also intended to provide novel intermediatesuseful for the preparation of tert-butyl3-methyl-4-oxopiperidine-1-carboxylate.

Solution to Problem

To achieve the above objects, the present invention provides a methodfor preparing a compound of the following formula IV, comprising a step(step 1) of preparing a compound of the following formula II byoptically resolving a compound of the following formula I:

According to an embodiment of the present invention, the preparationmethod of the present invention may further comprise a step (step 2) ofpreparing a compound of the following formula III by reacting thecompound of formula II with a base:

According to another embodiment of the present invention, thepreparation method of the present invention may further comprise a step(step 3) of preparing the compound of formula IV by reacting thecompound of formula III with ditert-butyl-dicarbonate.

According to still another embodiment of the present invention, thepreparation method of the present invention may further comprise, a step(step 4) of preparing the compound of formula I by racemizing anopposite enantiomer, which remains after preparing the desired opticallyactive compound of formula II in step 1, in the presence of a base, andrecycling the produced compound to step 1.

In the present invention, step 1 to step 4 as described above maygenerally be represented by Reaction Scheme 4 below:

Hereinafter, each step will be described in detail.

In the present invention, step 1 is a step of coupling the compound offormula I with a compound of the following formula V-1 or V-2:

The compound of formula V-1 or V-2 may be an anhydride or a hydrate.

In addition, a solvent that is used in step 1 is not limited and may beany solvent in which the reaction of step 1 may be performed. Forexample, the reaction of step 1 may be performed in methanol, ethanol,isopropanol, acetone, acetonitrile, ethyl acetate, dichloromethane,tetrahydrofuran, or a mixture solvent thereof.

Furthermore, the reaction of step 1 may be performed at a temperature of0 to 50° C., preferably 35 to 45° C.

In the present invention, the base that is used in step 2 above is notlimited and may be any base in which the reaction of step 2 may besolvent. For example, ammonium hydroxide, sodium hydroxide, potassiumhydroxide or lithium hydroxide may be used as the base. Furthermore, thepH is preferably adjusted to 9.8-10.5 by use of the base.

Moreover, a solvent that is used in step 2 is not limited and may be anysolvent in which the reaction of step 2 may be performed. For example,the reaction of step 2 may be performed in dichloromethane, ethylacetate, methyl ethyl ketone, or a mixture solvent thereof.

In addition, the reaction of step 2 may be performed at a temperature of15 to 30° C., preferably 23 to 28° C.

In the present invention, step 3 may be performed in the presence of apalladium catalyst. The palladium catalyst may be Pd/C, Pd(OH)₂, orPd(OH)₂/C.

In step 3, the reaction molar ratio between the compound of formula III,the palladium catalyst and the di-tert-butyl-dicarbonate may be 1:0.03:1to 1:0.5:5.

Furthermore, a solvent that is used in step 3 is not limited and may beany solvent in which the reaction of step 3 may be performed. Forexample, the reaction of step 3 may be performed in any one solventselected from the group consisting of methanol, ethanol, ethyl acetate,tetrahydrofuran, and mixtures thereof.

In addition, the reaction of step 3 may be performed at a temperature of20 to 35° C., preferably 23 to 28° C.

In the present invention, a base that is used in step 4 above is notlimited and may be any base in which the reaction of step 4 may beperformed. For example, sodium hydroxide, ammonium hydroxide, potassiumhydroxide or lithium hydroxide may be used as the base.

Furthermore, a solvent that is used in step 4 is not limited and may beany solvent in which the reaction of step 4 may be performed. Forexample, the reaction of step 4 may be performed in purified water,dichloromethane, toluene, ethyl acetate, methyl ethyl ketone, or amixture solvent thereof.

In addition, the reaction of step 4 may be performed at a temperature of20 to 40° C., preferably 25 to 35° C.

According to the preparation method of the present invention, opticallyactive tertbutyl 3-methyl-4-oxopiperidine-1-carboxylate (Formula IV) canbe prepared, and an optically active drug can be prepared using theprepared compound as an intermediate.

The preparation method of the present invention can prepare highly pureoptically active tert-butyl 3-methyl-4-oxopiperidine-1-carboxylate inhigh yield. In addition, the preparation method of the present inventioncan industrially produce large amounts of test-butyl3-methyl-4-oxopiperidine-1-carboxylate by using commercially availablereagents and solvents. Furthermore, since the preparation method of thepresent invention may comprise racemizing the opposite enantiomerremaining after the preparation of the compound of formula II and usingthe obtained racemate to prepare the compound of formula I, it canfurther increase the yield and is economic in that the loss of reagentscan be reduced.

The present invention provides a compound of the following formula IIand a compound of the following formula III, which are novelintermediates for the preparation of optically active tert-butyl3-methyl-4-oxopiperidine-1-carboxylate, and methods for preparing thesame:

The compound of formula II according to the present invention can beprepared through a step of optically resolving a compound of thefollowing formula I:

In the present invention, a method for preparing the compound of formulaII may be performed by the same process as the above-described step 1.

In addition, the compound of formula III according to the presentinvention can be prepared through a step of reacting the compound offormula II with a base. In the present invention, a method for preparingthe compound of formula III may be performed by the same process as theabove-described step 2.

The compound of formula II and compound of formula ITT according to thepresent invention are useful as intermediates for the preparation ofoptically active tert-butyl 3-methyl-4-oxopiperidine-1-carboxylate.

In the present invention, the compound of formula II is(R)-1-benzyl-3-methylpiperidin-4-one(2S,3S)-2,3-bis((4-methylbenzoyl)oxy)succinate, or(S)-1-benzyl-3-methylpiperidin-4-one(2R,3R)-2,3-bis((4-methylbenzoyl)oxy)succinate. In the presentinvention, optically active 2,3-bis((4-methylbenzoyl)oxy)succinic acidis used to optically resolve the racemic compound of formula I, and thecompound of formula II can be prepared with an optical purity of atleast 99% cc and in high yield. In addition, the undesired oppositeenantiomer remaining after preparing the compound of formula II can berecycled by simply racemizing it in the presence of a base as mentionedabove with respect to step 4 and using the racemate in the preparationof the compound of formula I, thereby increasing the overall processyield and reducing the production cost.

In the present invention, the compound of formula III is(R)-1-benzyl-3-methylpiperidin-4-one, or(S)-1-benzyl-3-methylpiperidin-4-one. In the present invention, thecompound of formula III can be prepared with an optical purity of atleast 99% ee and in high yield, like the compound of formula II, andthus the desired compound of formula IV can also be prepared with anoptical purity of at least 99% ee and in high yield.

Advantageous Effects of Invention

According to the preparation method of the present invention, largeamounts of highly pure optically active tert-butyl3-methyl-4-oxopiperidine-1-carboxylate can be industrially prepared inhigh yield by use of commercially available reagents and solvents.

In addition, using the novel intermediates of the present invention,highly pure optically active tert-butyl3-methyl-4-oxopiperidine-1-carboxylate can be prepared in high yield.

BEST MODE FOR CARRYING OUT THE INVENTION

Hereinafter, the present invention will be described in further detailwith reference to examples and experimental examples. It is to beunderstood, however, that these examples and experimental examples areintended to illustrate the present invention and the scope of thepresent invention is not limited by these examples and experimentalexamples.

Example 1: Preparation of (R)-1-benzyl-3-methylpiperidin-4-one(2S,3S)-2,3-bis((4-methylbenzoyl)oxy)succinate (Compound of Formula II)

278.0 kg of acetonitrile and 58.9 kg of 1-benzyl-3-methylpiperidin-4-onewere introduced into a reactor and warmed to 40±2° C. 129.0 kg of(2S,3S)-2,3-bis((4-methylbenzoyl)oxy)succinic acid hydrate was addedthereto. Stirring was performed at 40±2° C. for 12±2 hours. Afterfiltration, the residue was washed with 92.7 kg of acetonitrile. Theresulting material was dried under vacuum at 40° C. to afford the titlecompound (70.7 kg, 83%, 99% ee).

¹H-NMR (400 MHz, DMSO-d6): δ=0.84 (d, 3H), 2.16-2.40 (m, 2H), 2.45 (s,6H), 2.58-2.71 (m, 3H), 3.08-3.11 (m, 2H), 3.74 (s, 2H), 5.79 (s, 2H),7.27-7.40 (m, 9), 7.89 (d, 4H).

Optical rotation: [α]_(D) ²⁰=96.0°

([α]_(D) ²⁰: 20° C., D line of sodium spectrum (589 nm), 1% solution)

Example 2: Preparation of (S)-1-benzyl-3-methylpiperidin-4-one(2R,3R)-2,3-bis((4-methylbenzoyl)oxy)succinate (Compound of Formula II)

18.7 kg of acetonitrile and 3.4 kg of 1-benzyl-3-methylpiperidin-4-onewere introduced into a reactor and warmed to 40±2° C. 7.4 kg of(2R,3R)-2,3-bis((4-methylbenzoyl)oxy)succinic acid hydrate was addedthereto. Stirring was performed at 40±2° C. for 12±2 hours. Afterfiltration, the residue was washed with 5.3 kg of acetonitrile. Theresulting material was dried under vacuum at 40° C. to afford the titlecompound (4.0 kg, 81%, 99% ee).

¹H-NMR (400 MHz, DMSO-d6): δ=0.83 (d, 3H), 2.18-2.27 (m, 2H), 2.40 (s,6H), 2.56-2.72 (m, 3H), 3.09-3.13 (m, 2H). 3.74 (s, 2H), 5.79 (s, 2H),7.28-7.40 (m, 9), 7.89 (d, 4H).

Example 3: Preparation of (R)-1-benzyl-3-methylpiperidin-4-one (Compoundof Formula III)

469.1 kg of dichloromethane and 70.7 kg of the(R)-1-benzyl-3-methylpiperidin-4-one(2S,3S)-2,3-bis((4-methylbenzoyl)oxy)succinate prepared in Example 1were introduced into a reactor, and 353.5 kg of purified water was addedthereto, followed by stirring. The pH was adjusted to 10 by addition of26.2 L of ammonium oxide. The organic layer was separated and 353.5 kgof purified water was added thereto, followed by stirring. The organiclayer was separated, concentrated under vacuum at 40° C., andcrystallized from n-heptane to afford the title compound (22.4 kg, 92%,99.8% ee).

¹H-NMR (400 MHz, DMSO-d6): δ=0.85 (d, 3H), 2.03 (t, 1H), 2.16 (d, 1H),2.33 (t, 1H), 2.53-2.66 (m, 2H), 2.99-3.05 (m, 2H), 3.59 (s, 2H),7.25-7.35 (m, 5H).

Optical rotation: [α]_(D) ²⁰=18.3°

([α]_(D) ²⁰: 20° C., D line of sodium spectrum (589 inn), 1% solution).

Example 4: Preparation of (S)-1-benzyl-3-methylpiperidin-4-one (Compoundof Formula III)

26.4 kg of dichloromethane and 4.0 kg of the(S)-1-benzyl-3-methylpiperidin-4-one(2R,3R)-2,3-bis((4-methylbenzoyl)oxy)succinate prepared in Example 2were introduced into a reactor, and 19.9 kg of purified water was addedthereto, followed by stirring. The pH was adjusted to 10 by addition of1.5 L of ammonium hydroxide. The organic layer was separated and 19.9 kgof purified water was added thereto, followed by stirring. The organiclayer was separated and concentrated under vacuum at 40° C.Crystallization from n-heptane was performed to afford the titlecompound (1.2 kg, 89%, 99.5% ee).

¹H-NMR (400 MHz, CDCl₃): δ=1.04 (d. 3H), 2.08 (t, 1H), 2.32-2.54 (m,2H), 2.60-2.78 (m, 2H), 3.03-3.24 (m, 2H), 3.64 (S, 2H), 7.46 (s, 5H).

Example 5: Preparation of tert-butyl(R)-3-methyl-4-oxopiperidine-1-carboxylate (Compound of Formula IV)

141.6 kg of ethyl acetate and 22.4 kg of the(R)-1-benzyl-3-methylpiperidin-4-one prepared in Example 3 wereintroduced into a hydrogen reactor and completely dissolved by stirring.28.9 kg of di-tert-butyl dicarbonate and 1.12 kg of 10% palladium/carbonwere added thereto, followed by stirring. Stirring was performed for 24hours under controlled conditions of temperature of 25±2° C. andhydrogen pressure of 50 psi (3.7±0.2 atm). After completion of thereaction, the palladium/carbon was filtered out, and the residue wasconcentrated under vacuum at 40° C. 15.3 kg of n-heptane was added tothe concentrate, followed by cooling to 0±5° C. and crystallization. Theresulting material was dried under vacuum at room temperature to affordthe title compound (21.4 kg, 91%, 99.5% ee).

¹H-NMR (400 MHz, CDCl₃): δ=1.02 (d, 3H), 1.47 (s, 9H), 2.36-2.55 (m,3H), 2.55 (m, 1H), 3.24 (t, 1H), 4.15-4.19 (m, 2H).

Optical rotation: [α]_(D) ²⁰=−1.2°

([α]_(D) ²⁰: 20° C., D line of sodium spectrum (589 nm), 1% solution).

Example 6: Preparation of tert-butyl(S)-3-methyl-4-oxopiperidine-1-carboxylate (Compound of Formula IV)

7.7 kg of ethyl acetate and 1.2 kg of the(S)-1-benzyl-3-methylpiperidin-4-one prepared in Example 4 wereintroduced into a hydrogen reactor and completely dissolved by stirring.1.6 kg of di-tert-butyl dicarbonate and 0.06 kg of 10% palladium/carbonwere added thereto, followed by stirring. Stirring was performed for 24hours under controlled conditions of temperature of 25±2° C. andhydrogen pressure of 50 psi (3.7±0.2 atm). After completion of thereaction, the palladium/carbon was filtered out, and the residue wasconcentrated under vacuum at 40° C. 1.7 kg of n-heptane was added to theconcentrate, followed by cooling to 0±5° C. and crystallization. Theresulting material was dried under vacuum at room temperature to affordthe title compound (1.0 kg, 78%, 99.2% ee).

¹H-NMR (400 MHz, CDCl₃): δ=1.02 (d, 3H), 1.47 (s, 9H), 2.34-2.56 (m,3H), 2.70-2.89 (m, 1H), 3.22 (t, 1H), 4.16-4.19 (m, 2H).

Example 7: Preparation of 1-benzyl-3-methylpiperidin-4-one (Compound ofFormula I) by Racemization from Formula ent-II and Formula II (Recycle)

The filtrate remaining after preparing the compound of formula II(Example 1) was introduced into a reactor and concentrated under vacuumat 45° C. The concentrate was cooled to 0 to 5° C., and 83 L of 10% NaOHaqueous solution was added slowly thereto. The reaction solution waswarmed to 35 to 40° C. and stirred for 6 hours. 221.9 kg ofdichloromethane was added thereto, followed by stirring for 30 minutes,after which the organic layer was separated. 133.4 kg of dichloromethanewas added to the aqueous layer, followed by stirring for 30 minutes,after which the organic layer was separated. 59 kg of anhydrousmagnesium sulfate was added to the organic layer and stirred for 30minutes, followed by filtration. The residue was concentrated undervacuum at 40° C. to afford the title compound (23.6 kg, 80%).

¹H-NMR (400 MHz, CDCl₃): δ=0.85 (d, 3H), 2.02 (t, 1H), 2.16 (d, 1H),2.32 (t, 1H), 2.50-2.67 (m, 2H), 2.98-3.23 (m, 2H), 3.58 (s, 2H),7.23-7.36 (m, 5H).

Example 8: Preparation of 1-benzyl-3-methylpiperidin-4-one (Compound ofFormula I) by Racemization from Formula ent-II and Formula II (Recycle)

The filtrate remaining after preparing the compound of formula II(Example 2) was introduced into a reactor and concentrated under vacuumat 45° C. The concentrate was cooled to 0 to 5° C., and 4.8 L of 10%NaOH aqueous solution was added slowly thereto. The reaction solutionwas warmed to 35 to 40° C. and stirred for 6 hours. 12.8 kg ofdichloromethane was added thereto, followed by stirring for 30 minutes,after which the organic layer was separated. 12.8 kg of dichloromethanewas added to the aqueous layer, followed by stirring for 30 minutes,after which the organic layer was separated. 7.7 kg of dichloromethanewas added to the aqueous layer, followed by stirring for 30 minutes,after which the organic layer was separated. 3.4 kg of anhydrousmagnesium sulfate was added to the organic layer and stirred for 30minutes, followed by filtration. The residue was concentrated undervacuum at 40° C. to afford the title compound (1.3 kg, 75%).

¹H-NMR (400 MHz, CDCl₃): δ=0.85 (d, 3H), 2.02 (t, 1H), 2.16 (d, 1H),2.32 (t, 1H), 2.50-2.67 (m, 2H), 2.98-3.23 (m, 2H), 3.58 (s, 2H),7.23-7.36 (m, 5H).

The invention claimed is:
 1. A method for preparing a compound of the following formula IV, comprising a step (step 1) of preparing a compound of the following formula II by optically resolving a compound of the following formula I:


2. The method of claim 1, further comprising a step (step 2) of preparing a compound of the following formula III by reacting the compound of formula II with a base:


3. The method of claim 2, further comprising a step (step 3) of preparing the compound of formula IV by reacting the compound of formula III with di-tert-butyl-dicarbonate.
 4. The method of claim 2, further comprising a step (step 4) of preparing the compound of formula I by racemizing an opposite enantiomer, which remains after preparing the compound of formula II in step 1, in the presence of a base, and recycling the prepared compound of formula I to step
 1. 5. The method of claim 1, wherein step 1 comprises coupling the compound of formula I with a compound of the following formula V-1 or V-2:


6. The method of claim 1, wherein step 1 is performed in any one solvent selected from the group consisting of methanol, ethanol, isopropanol, acetone, acetonitrile, ethyl acetate, dichloromethane, tetrahydrofuran, or a mixture solvent thereof.
 7. The method of claim 1, wherein step 1 is performed at 0 to 50° C.
 8. The method of claim 2, wherein the base that is used in step 2 is selected from the group consisting of ammonium hydroxide, sodium hydroxide, potassium hydroxide, or lithium hydroxide.
 9. The method of claim 2, wherein the pH in step 2 is adjusted to 9.8-10.5.
 10. The method of claim 3, wherein step 3 is performed in the presence of a palladium catalyst.
 11. The method of claim 10, wherein the palladium catalyst is selected from the group consisting of Pd/C, Pd(OH)₂, or Pd(OH)₂/C.
 12. The method of claim 3, wherein step 3 is performed in any one solvent selected from the group consisting of methanol, ethanol, ethyl acetate, tetrahydrofuran, and mixtures thereof.
 13. The method of claim 4, wherein the base that is used in step 4 is selected from the group consisting of sodium hydroxide, ammonium hydroxide, potassium hydroxide, or lithium hydroxide. 